The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. Toward that end, this year, the Section on Integrative Neuroimaging has successfully executed comprehensive, multimodal positron emission and magnetic resonance based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo (medication-free) conditions as well as matched healthy individuals. Though this work is necessarily challenging to conduct, we have made substantial progress in data collection, which now includes characterization of dopamine-dependent mnemonic and reward-related neural responses, striatal presynaptic dopamine synthetic capacity, and both D1 and D2/3 receptor availability. This project has allowed us to identify and replicate specific schizophrenia-associated aberrancies of prefrontal activation and medial temporal lobe connectivity, suggesting frontal and temporal circuit disruption may be an important illness trait phenotype. In line with this assertion, recent work has shown that individuals with schizophrenia and, to a lesser degree, individuals harboring genetic risk for schizophrenia demonstrate abnormal hippocampal activation and connectivity during memory encoding (Rasetti et al., 2014). In evaluating contributing molecular mechanisms, we have found that candidate illness risk genes thought to regulate neuronal function in these same regions impact frontotemporal functional phenotypes and do so differently in those with schizophrenia relative to healthy volunteers. For instance, we have discovered that in medication-free patients with schizophrenia, but not healthy volunteers, there exists an inverse relationship between dorsolateral prefrontal cortical and medial temporal lobe blood flow, which is mediated by COMT genotype, an important determinant of cortical dopaminergic tone. We have similarly shown in dedicated regional cerebral blood flow studies of the hippocampus that medication-free patients with schizophrenia show abnormal hippocampal activity under multiple cognitive conditions, but only if they possess a particular BDNF genotype, previously associated with reduced activity-dependent BDNF release in hippocampal neurons. (Eisenberg et al., 2013) Together, this series of experiments elucidates a mechanistic explanation for variation in characteristic resting-state and cognitive challenge-related neural abnormalities previously identified in schizophrenia. With further accrual, we will soon be able to follow up on this body of work to test important hypotheses about the neurochemical basis of these signature dysfunctions in schizophrenia, which could potentially inform future therapeutics.